Optogenetic stimulation of medial septal glutamatergic neurons modulates theta-gamma coupling in the hippocampus

The oscillatory activity of the hippocampus and parahippocampal structures encodes information during cognition. Multiple researchers emphasize hippocampal cross-frequency theta-gamma coupling (TGC) as a basic mechanism for information processing, retrieval, and consolidation of long-term and working memory. While the role of entorhinal afferents in the modulation of hippocampal TGC is widely accepted, the influence of other main input to the hippocampus, from the medial septal area (MSA, the pacemaker of the hippocampal theta rhythm) is poorly understood. This area innervates multiple targets in the hippocampus, so information about the participation of MSA in cross-frequency interactions might be critical for an understanding of neural coding. Optogenetics allows us to explore how different neuronal populations of septohippocampal circuits control neuronal oscillations in vivo. It was shown that optogenetic activation of glutamatergic projections to the hippocampus with theta-frequency stimuli paces the hippocampal theta rhythm. Here we investigated the influence of phasic activation of MSA glutamatergic neurons expressing channelrhodopsin II on theta-gamma coupling in the hippocampus. Transgenic mice B6.Cg-Tg (Thy1-COP4/EYFP)18Gfng/J were used in this experiment. Expression of ChRII in MSA was verified immunohistochemically and the optic fibers just above MSA and the recording electrodes in the CA1 hippocampal field were implanted. During the experiment, local field potentials of MSA and hippocampus of freely behaving mice were modulated by 470nm light flashes with theta frequency (2-10) Hz. It was shown that both the power and the strength of modulation of gamma rhythm nested on hippocampal theta waves depend on the frequency of stimulation. The modulation of the amplitude of slow gamma rhythm (30-50 Hz) prevailed over modulation of fast gamma (55-100 Hz) during flash trains and the observed effects were specific for theta stimulation of MSA. We discuss the possibility that phasic depolarization of septal glutamatergic neurons controls theta-gamma coupling in the hippocampus and plays a role in memory retrieval and consolidation. ### Competing Interest Statement The authors have declared no competing interest.